DD264431A5 - PROCESS FOR THE PREPARATION OF BENZAZESINE DERIVATIVES - Google Patents

Abstract

Benzazecine cpds of the formula (I) and benzoquinoline cpds of the formula (II) are new. R1 and R2 are each independently H or Cl; R3 is H, F, Cl, Br or OCH3; R4 is H, Cl or OCH3, and two or three of R1, R2, R3 and R4 are H; R5 is H, acetyl, propionyl, benzoyl, chloro benzoyl, methoxybenzoyl or phenylacetyl Also in (I) R5 may be a cleavable gp (Z) other than the acyl. - Eighteen cpds (I) including 4-acetyl-9-chloro-1,2,4,5,6,7 - hexahydro-4-benzazecine-3,8-dione and the corresp 4-acetyl-9,11-dichloro, 4-propionyl-11-chloro, 4-(p-methoxybenzoyl) -11-chloro, 9-chloro, 11-chloro-4-phenylacetyl and 4-acetyl-11-bromo cpds are specifically claimed.

Description

68 003/18

Process for the preparation of benzazecine derivatives Field of application of the invention

The invention relates to a process for the preparation of benzazecine derivatives having valuable pharmacodynamic properties.

The compounds according to the invention are used as medicaments, for example to combat or prevent cerebral insufficiency or to improve cognitive functions (such as memory, learning ability, interest in the environment and self-care), for example in geriatrics, in intoxications, such as alcoholism, and in cerebro-vascular disorders (ie Meniere's disease) and developmental disorders (such as dysr lexia).

Characteristic of the known state of the art

There are known compounds which are used for the treatment of cerebral insufficiency or for the improvement of cognitive punctures. These compounds are mostly 2-pyrrolidinone derivatives, which are structurally very far removed from the 4-benzazecon-3-diones prepared according to the invention. 2-Pyrrolidiron derivatives of the type mentioned are described for example in CH-PS 436 304 and in EP-A-5143, 24030, 57846 imd 71216th

Object of the invention

The aim of the invention is the provision of novel compounds with a strong pharmacodynamic effect, which in particular

- la -

singles) are suitable for the treatment of ceribral insufficiency and for improving cognitlver functions,

Darlogunn of the essence , the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation,

According to the invention Be..iz.azecine derivatives are the general form of oil

C-CH ₂ - CH ₂

• CH _p - CH _p - C

- F 0

manufactured,

12 3

wherein R and R are each hydrogen or chlorine, R is hydrogen, fluorine, chlorine, bromine or methoxy, R is hydrogen, chlorine or methoxy and R is hydrogen, acetyl, propionyl, bonzoyl, chlorobenzoyl, methoxybonzyl or phenylacetyl, with the proviso that 2 or 3 of the symbols R to R are hydrogen.

These compounds are new and have valuable pharmacodynamic properties.

The present invention relates primarily to benzazecine derivatives of the general formula I as such and as active pharmaceutical ingredients, to processes and intermediates for the preparation of these benzazecin derivatives, to medicaments containing them and to the preparation of such medicaments, and to the use of benzazecin. Dorivaten the general formula I in the control or prevention of diseases or in improving health, especially in the control or prevention of cerebral insufficiency or in improving cognitive functions and the use of benzazecine derivatives of the general formula I. for the manufacture of medicines for the control or prevention of cerebral insufficiency bi.w. for the cognitive enhancement

Functions.

The term "lower" used in the present specification denotes radicals or compounds which contain at most 7, preferably at most 4, carbon atoms. The term "alkyl" refers to straight or branched chain saturated hydrocarbon radicals such as methyl, ethyl, n -propyl, isopropyl, η-butyl, isobutyl, s-butyl, t-butyl and the like. The term "acyl" refers to radicals which are derived from organic acids by elimination of the hydroxyl group and accordingly comprises e.g. Alkanoyl radicals (such as acetyl, propionyl and the like), aroyl radicals (such as benzoyl, p-chlorobenzoyl, o-methoxybenzoyl, m-methoxybenzoyl, p-methoxybenzoyl and the like), arylalkanoyl radicals (such as phenylacetyl and the like), etc.

Among the henzazecine derivatives of the general formula I are those in which R is chlorine and R, R and R are each hydrogen or R 'is chlorine and R, R and R are each hydrogen or R is fluorine, chlorine, bromine or methoxy and R, R and R is hydrogen or R chlorine

12 or methoxy and R, R and R are each hydrogen or

13 2

R and R are each chlorine and R and R are each hydrogen

mean. The preferred meaning of the symbol R in formula I is acetyl. Very particularly preferred compounds of the general formula I are:

4-Acetyl-9-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione.

4-acetyl-ll-chloro-1,2,4,5,6 _t 7-hexahydro-4-benzazecine-3,8-dione,

4-acetyl-ll-fluoro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione and

4-Acetyl-S ₍ II-dichloro-1, 2,4,5,6,7-hexahydco-4-benzazecine-3,8-dione, 15

Further preferred compounds of general formula I are:

4-acetyl-ll-raethoxy-l, 2,4.5,6.7-hexahydro-4-benzazecine-3,8 ~ dione,

ll-chloro-1,2,4,5,6,7-hexahydro-4-propionyl-4-benzazecine-3,8-dione,

4-benzoyl-II-chloro-1, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione, 4- (o-methoxybenzoyl) -ll-chloro-l, 2,4, 5,6.7-hexahydro-4-benzazecine-3,8-dione,

4- (r-methoxybenzoyl) -II-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione, 4- (p-methoxybenzoyl) -ll-chloro-l, 2, 4,5,6,7-hexahydro-4-benzazecine-3,8-dione,

II-chloro-4- (p-chlorobenzoyl) -1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione and

4-acetyl-l, 2,4,5,6,7-hexahydro-12-methoxy-4-benzazecine-3.8-dione. 35

2 ^ 443-1

Representative examples of compounds of formula I are also:

9-Chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione; 4-Aeetyl-10-chloro-l, 2.4,5.6,7-hexahydro-4-benzazecine-3,8-dione;

ll-chloro-l, 2,4,5,6,7-hexahydro-4- (phenylacetyl) -4-benzazecine-3,8-dione;

11-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione; 4-acetyl-11-bromo-1, / ;, 4,5,6,7-hexahydro-4-benzazec-3,8-dione; and

4-Acetyl-12-chloro-1,2,4,5,6,7-hexahydro-4-beni: azecine-3,8-dione.

The benzazecine-decane derivatives of general formula I can be prepared by reacting with

a) a benzoquinoline derivative of the general formula R ¹ / \

I 0 ι

R ^{3 /} V ^Ν · ^/

Wherein R, R, R, R and R have the meaning mentioned above, oxidized or

b) of a benzazecine derivative of the general formula

1 O ₂ I C-CH ₇ - CH ₂ \

I Il N-Z

^r3 1. ^c "2 ^-CH 2-i R ⁴ O

Wherein R, R, R and R have the meaning mentioned above and Z is a leaving group,

removed the group marked Z. 5

The compounds of the above formula II are novel and also the subject of the present invention, as well as a process for their preparation, which is characterized in that 10

a) a Benzochlnollnon-Derlvat the general formula

'V

\ A.A>

_R 3 / y Ny

R ⁴

wherein R, R, R and R have the meaning mentioned above, reduced or

b) a compound of the formula R ¹

vyv

12 3 4 where R, R, R, and R are the ones that have been included

Have meaning in the presence of a strong base with a compound of

general formula 35

where X is an exhaust group,

and, in effect, the resulting compound of general formula II, wherein R is hydrogen, duccb. Acetyl, Pcopionyl, benzoyl, chlorobenzoyl, methoxybenzoyl or phenylacetyl N-substituted.

Some dec benzoquinoline derivatives of general formula II have pharmacodynamic properties similar to those of the benzazecine derivatives of formula I, especially 10

4-Acetyl-8-chloro-l, 2,3,4,5,6-h6xahydcobenzo (fJ quinoline, 4-acetyl-10-chloro-1,2,3,4,5,6-hexahydrobenzo [f] quinoline and

8-chloro-4- (p-chlorobenzoyl) -1,2,3,4,5, ö-hexahydcobenio- [f] quinoline.

The present invention accordingly also pharroaxodynamically active benzoquinoline derivatives of the general formol II as pharmaceutical agents, these onthaltende drugs and the production of such drugs, and their use in the control or prevention of diseases or in the improvement of health, especially in Dec Control or prevention of cerebral insufficiency or in the improvement of cognitive functions and their use in the manufacture of medicaments for the control or prevention of cerebral insufficiency or for the improvement of cognitive functions.

Those among the compounds of formula III wherein Z is acetyl, propionyl, benzoyl, chlorobenzoyl, methoxybenzoyl or phenylacetyl fall within the scope of formula I; those among the compounds of formula III wherein Z has another meaning are also new

and also the subject of the present invention. 35

The oxidation according to the invention of benzoquinoline derivatives of the general formula II to give corresponding benzazex

Cin derivatives of the general formula I are expediently carried out by means of m-Chlocpecbenzoesäuce in an inert organic solvent, for example in a Halogeniecten hydrocarbon such as chloroform and the like. The temperature is not critical, and the oxidation may conveniently be carried out at temperatures of about -20 ⁰ C to about 30 ⁰ C, preferably between about -5 ° C and about room temperature.

Furthermore, this oxidation can also be conveniently carried out by means of potassium permanganate and sodium periodate, conveniently in a Zweiphasensyetem consisting of water and a thus immiscible organic solvent, such as a halogenated Kohlwaeserstoff, such as methylene chloride and the like. In this case, a phase transfer catalyst is advantageously added, in particular a quaternary ammonium salt, such as benzyltitanium ammonium chloride and the like. Again, is not critical, the reaction temperature and the oxidation by means of potassium permanganate / sodium can be carried out conveniently between about 0 ⁰ bsi temperatures C and about 30 ⁰ C., conveniently at about room temperature.

Oxidizing agents or oxidation systems such as peracetic acid, hydrogen peroxide and formic acid or p-toluenesulfonic acid, chromic acid, Jones reagent and the like are also suitable for carrying out the oxidation in question.

If R in formula II means hydrogen, then

the oxidation to the corresponding benzazecine derivative of Forml I is extremely easy, possibly even spontaneously by the action of the oxygen present in the air.

Benzazecine derivatives of the general formula I can also be obtained according to the invention by reacting a benzazecine derivative of the general formula III with

Z designated cleavable group removed. Ale cleavable groups are primarily readily cleavable acyl groups such as acetyl and the like.

The cleavage of an acetyl group is conveniently carried out under alkaline conditions, for example by means of potassium carbonate, sodium bicarbonate and the like in a mixture of water and a miscible organic solvent (eg a lower alkanol, such as methanol), by means of a lower alkali metal alkoxides in a inert under the reaction conditions organic solvents, usefully in the corresponding lower alkanol. etc..

The erfindungegemässe reduction of a Benzochinolinon- derivative of the general formula IV to the corresponding benzoquinoline dorivative of the general formula II. Wherein R ^{J is} hydrogen, is zweckmäesigerweiee means of a complex hydrides, such as lithium aluminum hydride and the like, in an inert organic solvent under the reaction conditions, conveniently in an ether such as tetrahydrofuran, dioxane and the like. The reaction temperature is not critical, and the reduction in question can be carried out at temperatures between about room temperature and about 12O ° C, conveniently at reflux temperature.

The erfindungegemässe reaction of a compound of formula V with a compound of formula Vi is carried out in the presence of a strong base, conveniently in the presence of an inorganic base such as potassium or sodium hydroxide, a quaternary ammonium base, such as benzyltrimethylammonium hydroxide and the like. The leaving group designated by the symbol X in formula VI is conveniently a halogenator, in particular a chlorine atom, but equivalents of other leaving groups are also suitable, e.g. Alkylsulfonyloxy groups, such as mesyloxy, arylsulfonyloxy groups, such as

2 "4431

Benzenesufonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy and the like. The compound of formula VI is zweckmäseigerweise used in the form of an acid addition salt, for example as the hydrochloride. The reaction is carried out in the presence of an organic solvent inert under the reaction conditions, for example, in a lower alkanol such as methanol, an aromatic hydrocarbon such as toluene, and the like.

The reaction is not critical, and the

Reacting the compounds of formula V and VI can conveniently be carried out between temperatures of from about 3O ° C and about 110 ⁰ C, preferably at reflux temperature.

Both in the reduction of a benzoquinolinone derivative of the general formula IV and in the reaction of compounds of the formula V and VI corresponding compounds of general formula II, wherein R is hydrogen. According to the invention, these can be correspondingly N-acylated, conveniently in situ, ie. without being caught. The acylating agent used here is the desired acyl radical-yielding reactive derivatives of the corresponding carboxylic acids, expediently anhydrides, such as acetic anhydride, propionic anhydride and the like, carboxylic acid chlorides, such as benzoyl chloride, p-chlorobenzoyl chloride, o-methoxybenzoyl chloride, m-methoxybenzoyl chloride, p-methoxybenzoyl chloride, phenylacetyl chloride, etc., and the same. Analogously, compounds of formula III are obtained which do not fall within the scope of general formula I, i. wherein Z is other than acetyl, propionyl, benzoyl, chlorobenzoyl, methoxybenzoyl or phenylacetyl, namely by treating corresponding compounds of general formula II wherein R is hydrogen with an agent providing the desired group Z, for example by means of benzyloxycarbonyl chloride and the like.

The production of compounds of the more general. formulas

IV and V is suitably carried out according to the following reaction scheme, wherein R, R, R and R have the meaning mentioned above and R and R are each lower alkyl or together with the nitrogen atom is a heterocyclic radical, such as pyrrolin-1-yl. Pyrrolidin-1-yl, piperidino, morpholino. 4- (lower alkyl) piperazine-1-yl and the like.

R ¹ 2 I Ii \

- 11 -

scheme

443

ί η ί viii

R ¹ OH

ι ϊ ϊ ί

VV

R ^J I \

R ~

T ii ί

Φ ·

20 ^R _R 4

T ß ³ * VII

R ² \. ^/O

ϊ Γ. T

Il ϊ V

^: Ί

R ¹ R ⁶

, A /% X _Ί

• · · 7

IJ I R

, 4 XII

^r4 I

R K

¹ '

I Il I ⁴ IV

- 12 -

Compounds of formula V may be prepared in one step from compounds of formula VII, by reaction with ethylene in the presence of aluminum chloride or another Lewis acid suitable for such reactions as a catalyst. The reaction takes place in the presence of an organic solvent which is inert under the reaction conditions, conveniently in a halogenated hydrocarbon, such as methylene chloride.

However, compounds of the formula V can also be prepared by a multistage synthesis starting from compounds of the formula VIII. First, the compound of formula VIII is reduced to the corresponding compound of formula IX, suitably with a complex hydride such as sodium borohydride or the like. The resulting compound of formula IX is then dehydrated to the corresponding compound of formula X, conveniently under acidic conditions, e.g. by means of a strong acid, such as p-toluenesulfonic acid or the like, in a water-immiscible, but azeotropically distilling solvent at Rückflussteraperatur, wherein the resulting water is removed continuously. The compound of formula X is then oxidized to the corresponding compound of formula XI. This oxidation is conveniently carried out by means of m-chloroperbenzoic acid or the like in an inert organic solvent under the reaction conditions, for example in a chlorierian hydrocarbon such as methylene chloride. Compounds of the formula V are then obtained starting from corresponding compounds of the formula XI, for example by treatment with an ethereal solution of magnesium bromide or by treatment with an organic sulphonic acid, such as p-toluenesulphonic acid or the like, in an inert organic solvent, such as

Toluene or the like

 35

To prepare a compound of the formula XII, a corresponding compound of the formula V is reacted with a second

7

amine of the formula HNR R such as pyrrolidine, in the presence of an acid, suitably an organic sulfonic acid such as p-toluenesulfonic acid or the like, in an inert organic solvent under the reaction conditions, for example in an aromatic hydrocarbon such as benzene; The resulting water is removed from the reaction system, for example by adding molecular sieve or by azeotropic distillation. Compounds of formula IV are obtained by reacting a corresponding compound of formula XII with acrylamide, conveniently in the presence of an acid, eg, an organic sulfonic acid such as p-toluenesulfonic acid, an acidic ion exchanger, or the like Temperatures of about i00 ° C to about 200 ⁰ C, conveniently from about 100 ~ 150 ° C, wherein as a solvent lower alkanols, such as ethanol or the like can be used.

As mentioned in the beginning, the benzacecine derivatives of the formula I are novel compounds with extremely valuable pharmacodynamic properties, and the same also applies to some of the benzoquinoline derivatives of the formula Ii. They are of low toxicity and have been shown to counteract experimentally induced cerebral insufficiency in the animal experiment described below.

The test apparatus is a "Skinner box" with an electrified grid floor (30 χ 40 cm) and a gray plastic Plat.tform (15 χ 15 χ 0.8 cm) in the corner right front. Inexperienced male rats (100-120 g) are placed individually on the platform. As soon as they descend to the grid floor, they receive an electrical foot shock (0.8 mA). The normal reaction of inexperienced rats is to jump back to the platform. However, as the rats are always trying to climb down again, the foot shock procedure for each animal must be three to five

- 14 -

to be repeated. After these three to five repetitions per animal, the rats have learned a so-called "passive avoidance response", i. they no longer try to descend to the grid floor because they know they will be punished.

Immediately thereafter, three groups of animals are formed. The first group receives an injection (i.p.) of 0.3 mg / kg scopolamine and distilled water (2 ml / kg p.o.). The second group receives, an injection (i.p.) of 0.3 mg / kg scopolamine and an oral dose of the test substance. Finally, the third group receives distilled water (p.o.).

2 hours later, each rat is placed once on the platform in the "Skinner box". The criterion for judging this test to determine a short-term memory effect is whether or not the animal stays on the platform for 60 seconds (the result may therefore be "yes" or "no" for each animal). The statistical significance of the differences between the results obtained in the first and second groups is determined by the chi-square test.

70-75% of animals treated with distilled water only (p.o.) still remember to stay on the platform 2-4 hours after learning the "passive avoidance response". In 85-92% of the animals treated with scopolamine (0.3 mg / kg i.p.) and distilled water (p.o.), a retrograde effect on the short-term memory lasts for 3-4 hours, i. they forgot they had to stay on the platform. A substance that is able to counteract cerebral insufficiency may relieve the short-term memory blockade caused by injection (i.p.) of 0.3 mg / kg scopolamine. A dose of a preparation is then considered active against scopolamine if the number of positive

- 15 -

tivon results ("yes") are significantly different from those with scopolamine (0.3 mg / kg i.p.) and only distilled water (p.o.) treated control animals.

The following table indicates at which doses certain compounds of formulas I and II show significant activity in the experiment described above. The table also contains data for the acute toxicity (DIi ₅₀ mg / kg for single oral administration).

reaching mice).

- 16 -

Table e

formula R ¹ R ² K ³ R ⁴ R ⁵ Significantly effective DL 50 same doses mg / kg p.o. rag / kq d.O. I Cl H H H COCH3 0.1 0.3 1 3 10 30 > 5000 I H H ci H COCH3 0.001 0.003 0.01 0.03 > 3000

I (H H P H COCH3

I Cl H Cl H COCH3 II H H Cl H COCH3 II Cl H H H COCH3

> 50G0 > 5000 2500-5000 0.03 0.1 0.3 1 3 10 12:03 0.1 0.3 1 0.01 12:03 0.1 0.3 0.3 1 3 10

" ₁₇ _ 2 6 4 4 3

The compounds of Formula I and pharmacokinetic active compounds of Formula II may be any of remedies, e.g. in Focm pharmaceutical preparations, find use. The pharmaceutical preparations may be administered orally, e.g. in the form of tablets, cheat tablets. Drayees, Haet and soft gelatin capsules. Solutions, emulsions or suspensions. The administration may also be rectal, e.g. in the form of suppositories, or parenteral, e.g. in the form of injection solutions.

As mentioned above, medicaments comprising a compound of the formula I and / or a pharmacodynamically active compound of the formula II are likewise the subject of the present invention, furthermore a process for preparing such medicaments, which is characterized in that one or more Compounds of formula I and / or pharmakodynamiech effective compounds of formula II and, if desired, brings one or more other therapeutically active substances together with one or more therapeutically inert excipients in a galenic dosage form.

For the production of tablets, coated tablets, dragees

and hard gelatin capsules may be prepared as excipients e.g. Lactose. Corn starch or derivatives thereof, talc, stearic acid or its salts, etc.

For soft gelatin capsules, suitable excipients are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

For the preparation of solutions and syrups are suitable as

Excipients e.g. Water, polyols, sucrose, invert sugar, glucose and the like

 35

- 18 -

Injection solutions are useful as excipients e.g. Water, alcohols, polyols, glycerin, vegetable oils, etc.

For suppositories are suitable as excipients e.g. natural or hardened oil. Waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations may also contain preservatives, dissolving agents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents. Salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable substances.

According to the invention, the compounds of the formula I and / or pharmacodynamically active compounds of the formula II can be used in the control or prevention of cerebral insufficiency or improvement of cognitive functions (such as memory capacity, learning ability, interest in the environment and self-care) in geriatrics, in intoxications such as alcoholism, and in cerebro-vascular disorders; Possible further areas of use are vestibular disorders (such as Meniere's disease) and developmental disorders (such as dyslexia), which can vary within wide limits and, of course, in individual cases, can be adapted to individual circumstances. In general, a daily dose of about 10 to 2500 mg should be appropriate when administered orally, but the above upper limit may be exceeded, should this prove appropriate.

Finally, the invention also relates to the use of the compounds of the formula I and / or of pharmacodynamically active compounds of the formula II for the preparation of medicaments for combating or preventing cerebral insufficiency or for improving cognitive function

features » Execution boispiol

The invention will be explained below in some places.

In the following examples, which illustrate the present invention but are not intended to limit its scope in any way, all temperatures are given in degrees centigrade »

example 1

a) 2u 218 g of aluminum chloride in 1000 ml of methylene chloride are added dropwise with stirring between O ⁰ and 5 within 1 hour 154.8 g of 2-chloro-phenylacetylchlorid, dissolved in 290 ml of methylene chloride, then in dos mixture between 0 ° and 5 Aethylon was introduced for 40 minutes, whereupon the reaction mixture was stirred for 1 hour at room temperature and then treated with 570 ml of cold water between 0 ° and 5 °. The methylene chloride phase was treated with 2 × 500 ml 2N hydrochloric acid, 2 × 500 ml sodium bicarbonate solution and 700 ml The water phases are extracted with 300 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulfate and concentrated in vacuo. The 8-chloro-3,4-dihydro-2- (1H) -naphthalenone crystallized from 400 ml of low boiling petroleum ether shows a Melting point of 56 ~ 59 ·

b) 70.0 g of 8-chloro-3,4-dihydro-2 (1H) -naphthalenone are dissolved in

26443

- 19a -

550 ml of benzene and 33 ml of pyrrolidine refluxed in the presence of 1.4 g of p-toluenesulfonic acid 2.5 times. The resulting crude 1- (8-chloro-3,4-dihydro-2-naphthyl) -pyrrolidine is purified without purification further processed "

c) 56.0 g of aorylamide and 3.0 g of anhydrous p-toluenesulfonic acid are added to 89.4 g of crude 1- (8-chloro-3,4-dihydro-2-naphthyl) -pyrrolidine hours at 100 ° and 150 ° "The R _e · aktionsge mixing is between 300 ml and 200 ml of water Methylonchlorid» oils organic phase is washed with water and

- 20 -

filtered through 500 g of silica gel (particle size 0.2-0.5 mm). The leached with Essigteeter lO-chloro-1,4,5,6-tetrahydrobenzo [h] -quinoline-3 (2H) -one shows after recrystallization from ethyl acetate a melting point of 186-187 °.

d) To a stirred under nitrogen suspension of 6.49 g Lithiumaluminiurohydrid in 240 ml of dry tetrahydrofuran within 35 minutes between 20 ° and 25 ° portionwise 20.0 g of 10-chloro-l, 4.5, 6-teti: ahydrobenzo [h] quinoline-3 (2H) -one added. The reaction mixture is then heated to reflux for 150 minutes under reflux, then cooled and then added between 0 ° and 10 ° with 21.0 ml of 6.5N sodium hydroxide solution. The resulting suspension is filtered, followed by washing the Filterrücketand several times with 20 ml of tetrahydrofuran and the filtrate is evaporated in vacuo. The resulting 10-chloro-1,2 ', 3,4,5,6-hexahydrobenzo [f] quinoline is processed further directly.

e) 20.1 g of crude 10-chloro-1,2,3,4,5,6-hexahydrobenzo [f] quinoline are taken up in 40 ml of pyridine and 36 ml of acetic anhydride. The reaction mixture is allowed to stand at room temperature for 20 hours, evaporated, the remaining residue is taken up twice in 150 ml of dry toluene and the resulting solutions evaporated to dryness. The residue is dissolved in methylene chloride and chromatographed on 150 g of silica gel (particle size 0.2-0.5 mm). The chloroform-eluted 4-acetyl-10-chloro-l, 2,3,4,5,6-hexahydrobenzo [fJquinoline shows after recrystallization from isopcopyl ether a melting point of 117-118 °.

f) 8.5 g of 4-acetyl-10-chloro-l, 2,3,4,5,6-hexahydrobenzo [f] -quinoline are dissolved in 205 ml of chloroform, whereupon at 0 ° to + 5 ° 16 g of 85 % m-chloroperbenzoic acid dissolved in 205 ml of chloroform is added dropwise. After 4-3tündigem stirring at room temperature, 4 g of potassium iodide and 70 ml of water are added to the reaction mixture, whereupon until the

- 21 -

Decolorization with Nattiumthioeulfat added. The chloroform phase is washed with 70 ml of 2N sodium hydroxide solution and 2 × 170 ml of heat. The water phases are shaken out with 170 ml of chloroform. The combined chloroform extracts are dried and evaporated in vacuo. The residue is dissolved in methylene chloride and chromatographed on 100 g of silica gel (Korngcöeae 0.2-0.5 mm). The methylene chloride-eluted 4-acetyl-9-chloro-l, 2,4,5,6,7-hexahydro-4-benzo ~ zecine-3.8-dione shows after recrystallization from isopropyl ether has a melting point of 115-116 °.

Example 2

7.60 g of 4-acetyl-9-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione are dissolved in 240 ml of methanol and washed with a mixture of 36 ml of methanol and 4 ml of saturated potassium carbonate solution. The mixture is stirred for 1 hour at room temperature and then the solvents are removed in vacuo. The residue is stirred in ethyl acetate; the crystallized 9-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione is filtered off and shows a melting point of 211-214 °. The filtrate is chromatographed on 100 g of silica gel (particle size 0.2-0.5 mm). From the egg white ester eluate an additional portion of 9-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione can be isolated.

Example 3

5.0 g of 8-chloro-3,4-dihydro-2 (1H) -naphthalenone, 115 ml of benzene and 17 ml of Triton-B (40% in methanol) are added to the residue; boiled, whereupon 5.0 g of 3-chloropropylamine hydrochloride, dissolved in 25 ml of methanol, added dropwise and heated for a further 5 hours at reflux. Then 5 g of molecular sieves 4A are added, followed by refluxing for an additional 20 hours. The reaction mixture is concentrated after filtration in a water-jet vacuum, whereupon the residue is partitioned between diethyl ether and 3N hydrochloric acid

- 22 -

26 443 I

and the organic phase extracted twice more with 3N hydrochloric acid. The hydrochloric acid phases are basified with 2N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate phases are washed with sodium chloride solution, dried and evaporated in vacuo. The residue is chromatographed through 300 g of silica gel (particle size 0.2-0.5 r.) Chroraato ^. The 9-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3.8-dione eluted with methylene chloride Essssigester (mixture 1: 1) and ethyl acetate shows a melting point of 196-198 after stirring in diethyl ether °. After recrystallization from ethyl acetate, the product has a melting point of 207-208 °.

In the above example, first of all lO-chloro-1,4,5,6-tetrahydrobenzo [h] quinoliu-3 (2H) -one is formed, which is not isolated, but by air oxidation in 9-chloro-1.2.4, -5 , 6,7-hexahydro-4-benzazecine-3,8-dione.

Example 4

α) 11.0 g of 7-chloro-3,4-dihydro-2 (1H) -naphthalenone is refluxed in 200 ml of benzene and 6.0 ml of pyrrolidine in the presence of 0.25 g of p-toluenesulfonic acid for 2 hours. The obtained 1- (7-chloro-3,4-dihydro-2-naphthyl) pyrrolidone is recrystallized from 150 ml of isopropyl ether and shows a melting point of 115-116 °.

b) To 10.6 g of 1- (7-chloro-3,4-dihydro-2-naphthyl) pyrrolidine was added 6.45 g of acrylamide. It is heated under nitrogen for 2 hours at 100 ° and 150 °. 100 ml of ethyl acetate are added to the reaction mixture, whereupon the mixture is stirred at room temperature and the 9-chloro-l, 4,5,6-tetrahydrobenzo [f] quinolin-3 (2H) -one is filtered off, which after recrystallization from ethyl acetate at 265.degree. 267 °

melts

 35

(c) To a suspension of 1.59 g of lithium aluminum hydride stirred at 20 ° under nitrogen in 60 ml of dry tetra-

- 23 -

hydrofuran are added over a period of 35 minutes between 20 ° and 25 °, 4.9 g of 9-chloro-l, 4,5,6-tetrahydrobenzo []] quinoline-3 (2H) -one in portions. The reaction mixture is refluxed anechliess for 150 minutes, then cooled and then treated between 0 ° and 10 ° with 5.20 ml of 6.5N sodium hydroxide solution. The resulting suspension is filtered, followed by washing the Filterrücketand several times with 20 ml of tetrahydrofuran and the filtrate is evaporated in vacuo. The resulting 9-chloro-benzo [f] quinoline is taken up as a crude product in 10 ml of pyridine and 9.0 ml of acetic anhydride. The reaction mixture is allowed to stand at room temperature for 20 hours, then evaporated, the remaining residue is taken up twice every 50 ml of dry toluene and the resulting solutions are evaporated to dryness. The residue is dissolved in methylene chloride and chromatographed on 150 g of silica gel (particle size 0.2-0.5 mm). The methylene chloride-eluted 4-acetyl-9-chlorobenzotf-quinoline shows, after recrystallization from isopropyl ether, a melting point of 151.5-152 °.

d) 2.5 g of 4-acetyl-9-chlorobenzo [f] quinoline are dissolved in 60 ml of chloroform, whereupon at 0 ° to + 5 °, 5.02 g of 85% m-chloroperbenzoic acid, dissolved in 60 ml of chloroform, dropwise be added. The mixture is then stirred at room temperature for 3 hours. 0.4 g of potassium iodide and 40 ml of water are added to the reaction mixture, whereupon sodium thioe sulfate is discolored until discolored. The chloroform phase is separated off and washed with 40 ml of 2N sodium hydroxide solution and then with 2 × 50 ml of water. The water phases are shaken out with 100 ml of chloroform. The combined chloroform extracts are dried and evaporated in vacuo. The recrystallized from isopropyl ether 4-acetyl-lO-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione shows a

Melting point of 136-137 °

 35

- 24 - 2 6 4 4 3

Example 5

a) To 230 g of aluminum chloride in 1050 ml of methylene chloride are added dropwise with stirring between 0 ° and 5 ° within 60 minutes 149.4 g of 4-Fluororphenylessigsäurechlorid dissolved in 300 ml of methylene chloride. Thereafter, in the mixture between 0-5 ° for 30 minutes, ethylene is introduced, whereupon stirring is continued for 1 hour at room temperature and then added between 0 ° and 5 ° within 30 minutes with 600 ml of ice water. The methylene chloride phase is washed with 2N hydrochloric acid, water and saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue is combined with 250 ml of low-boiling petroleum ether. leaves overnight in the refrigerator and filtered to the 6-fluoro-3,4-dihydro-2 (lH) -naphthalenone melting at 50-60 °.

b) IC, 7 g of 6-fluoro-3,4-dihydro-2 (1H) -naphthalenone are refluxed in 200 ml of benzene and 8.4 ml of pyrrolidine in the presence of 0.35 g of anhydrous p-toluenesulfonic acid for 2.5 hours. The resulting crude 1- (6-fluoro-3,4-dihydro-2-naphthyl) pyrrolidine is treated without further purification with 10.8 g of acrylamide and 0.5 g of p-toluenesulfonic acid. It is heated under nitrogen for 2 hours at 100 ° and 150 °. The reaction mixture is dissolved in 180 ml of chloroform and washed with water. The organic phase is filtered while eluting with chloroform over 150 g of silica gel (particle size 0.2-0.5 mm). Recrystallization from ethyl acetate gives 8-fluoro-l, 4,5,6-tetrahydrobenzo [h] quinoline-3 (2H) -one of melting point 223-224 °.

c) To a stirred at 20 ° under nitrogen suspension of 2.17 g of lithium aluminum hydride in 60 ml of dry tetrahydrofuran within 35 minutes between 20 ° and 25 ° in portions 6.2 g of 8-fluoro-l, 4,5,6, tetrahydrobenzo [h] quinolin-3 (2H) -one was added. The reaction mixture is then boiled under reflux for 150 minutes

- 25 -

chilled, then cooled and then added between 0 ° and 10 ° with 7.0 ml of 6.5N sodium hydroxide solution. The resulting suspension is filtered, after which the filter residue is washed several times with 20 ml of tetrahydrofuran each time and the filtrate is evaporated in vacuo. The resulting 8-fluoro-l, 2,3,4,5,6-hexahydrobenzotf-quinoline is processed directly

d) 6 g of crude 8-fluoro-l, 2,3,4,5,6-hexahydrobenzo [f] quinoline are taken up in 13 ml of pyridine and 2 ml of acetic anhydride. The reaction mixture is left to stand for 20 hours at room temperature, then evaporated, the remaining residue is taken up twice in 50 ml of dry toluene and the resulting solutions are evaporated to dryness. The residue is dissolved in methylene chloride and chromatographed on 150 g of silica gel (particle size 0.2-0.5 mm). The methylene chloride-eluted 4-acetyl-8-fluoro-1,2,3,4,5,6-hexahydrobenzo [f-quinoline, after recrystallization from isopropyl ether, has a melting point of 101-102 °.

e) 2.48 g of 4-acetyl-u-fluoro-1,2,3,4,5,6-hexahydrobenzo [f] -quinoline are dissolved in 60 ml of chloroform, whereupon at 0 ° to + 5 ° 5.24 g of 85% m-chloroperbenzoic acid dissolved in 40 ml of chloroform are added dropwise. Thereafter, the mixture is stirred for 3 hours at room temperature, 1.10 g of potassium iodide and is added to water and ml until the discoloration with sodium thiosulfate. The chloroform phase is separated off and washed with 15 ml of 2N sodium hydroxide solution and 2 × 40 ml of water. The uSascriyen extracts were shaken out with 20 ml of chloroform. The combined chloroform extracts are dried and evaporated in vacuo. The ethyl acetate-recrystallized 4-cetyl-ll-fluoro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione shows a melting point of 161-162 °.

Example 6 35

a) 1155 g (6.4 mol) of 6-chloro-3,4-dihydro-2 (1H) -naphthalenone are dissolved in 5 liters of toluene, and 500 g (7.0 mol) of pyrrolide are added dropwise.

- 26 -

din and then a solution of 26 g (0.14 mol) of p-Toluol8Ulfonsäuro in toluene and boils under reflux. When about 120 ml of water are separated, distilled from 4 1 of toluene and allowed to cool slowly. In the process, a solid crystallizes out. Filtration and washing with acetone gives 1- (6-chloro-3,4-dihydro-2-naphthyl) pyrrolidine of melting point 117-118 °.

Concentration of the mother liquor, suspension of the residue in ether, filtration and washing with acetone gives another portion of the above product of melting point 117-118 °.

b) 7Cl g (3 mol) of 1- (6-chloro-3,4-dihydro-2-naphthyl) pyrrolidine and 640 g (19 mol) of acrylamide in 7 1 ethanol with addition of 70 g of Amberlite IR200 are boiled for 3 days under reflux, the precipitated solid is filtered off, crystallized extractively with dioxane and receives 8-chloro-l, 4,5,6-tetrahydroben2o [f] quinoline-3 (2H) -one from the molten point 228-230 ° C.

c) 147 g (1.94 mol) of lithium aluminum hydride in 4 l of tetrahydrofuran are suspended under argon, 454 g (1.94 mol) of 8-chloro-l, 4,5,6-tetrahydrobenzo [f-quinoline-3 (2H ) -on and boil for 2.5 hours under reflux. Then it is cooled, dripping 470 ml of 18 percent. Sodium hydroxide solution, stirred for 30 minutes at room temperature, filtered and washed the filter residue with tetrahydrofuran. Evaporation of the filtrate gives 8-chloro-1,2,4,4,5,6-hexahydrobenzo [f] -

quinoline as a yellow oil

 30

d) 229 g (1.04 mol) of 8-chloro-1.2.3.4, 5,6-hexahydrobenzof-quinoline are dissolved in 2 l of methylene chloride, treated with 115 g (1.14 mol) of triethylamine, and 89.5 g are added dropwise at 0 ° (1.14 mol) of acetyl chloride in 400 ml of methylene chloride. After 1 hour of RUhron at room temperature, the mixture is poured into water, extracted with methylene chloride and the methylene chloride phase is dried with magnesium sulfate. Distilling off the

Solvent in vacuo gives a crude product, which is suspended in BOO ml of ether and filtered off. This gives 4-acetyl-8-chloro-l, 2,3,4,5,6-hexahydrobenzo [f] quinoline of melting point 106-108 °. Concentration of the mother liquor and Chroraatographieren (Kieeolgel / chloroform) gives another portion of melting point 106-108 °.

4-Acyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo [f-quinoline can also be prepared from 6-chloro-3,4-dihydro-2 (1H) -naphthalenone as follows:

100 g of G-chloro-3,4-dihydro-2 (1H) -naphthalenone (0.55 mol) in 2 liters of toluene are dissolved under argon, mixed with 64.0 g of powdered potassium hydroxide, heated to boiling temperature, and added in portions over 30 minutes 165 g of 3-chloropropylamine hydrochloride and koct.t on the water until the DUnnschichtchromatogramm no more educt is to be detected. After cooling to room temperature, 155 ml of triethylamine are added. Under ice cooling, so that an internal temperature of 25 ° is not exceeded, is added dropwise 60 ml of acetyl chloride, dissolved in 450 ml of toluene. The mixture is stirred for 1 hour at room temperature, extracted with water / methylene chloride, dried with magnesium sulfate, the solvent is distilled off in vacuo and 4-acetyl-8-chloro -i, 2,3,4,5,6-hexahydrobenzo [fJ- quinoline in the form of brown crystals which can be used as the crude product for the reaction described below.

e) Dissolve 115 g (0.44 mol) of 4-acetyl-8-clilor-1,2,3,4,5,6- hexahydrobenzoff-quinoline in 1 l of methylene chloride and dropwise at 0 °, a suspension of 189 g (0.93 Mole) of m-chloroperbenzoic acid (85%) in 500 ml of methylene chloride. After stirring for 1 hour at room temperature, the precipitate formed is filtered off and extracted with 2N sodium hydroxide solution and with water. Dry the organic phase with magnesium sulfate, distilling off the solvent in vacuo and recrystallizing the residue from ethyl acetate-ether

- 28 -

26 4 43

gives 4-acetyl-ll-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione as white crystals of melting point 154-156 °.

Example 7

a) Dissolve 8.40 g (0.038 mol) of 8-chloro-l, 2,3,4,5,6-hexahydcobenzo [C] quinoline in 20 ml of pyridine and stop at 0 ° 23.4 g (0.172 mol) Propionic anhydride to. After stirring over

Night at room temperature, extract with water and

Essigester, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica gel, chloroform-hexane 3: 1) and crystallization (Eseigester) gives 4-propionyl-8-chloro-l, 2,3,4,5,6-hexahydrobenzo [f] -quinoline as white crystals of melting point 115- 117 °.

b) Dissolve 7.85 g (0.028 mol) of 4-proponyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo [f] quinoline in 80 ml of chloroform and dropwise at 0 ° a suspension of 11.6 g (0.058 mol) of 85% strength m-chloroperbenzoic acid in 100 ml of chloroform. After 3-ündündigem stirring at room temperature, extracted with 2N sodium hydroxide solution and water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Crystallization from ethyl acetate ether gives 11-chloro-l, 2,4,5,6,7-hexahydro-4-propionyl-4-benzazecine-3,8-dione as white crystals of melting point 149-151 °.

Example 8

a) Dissolve 7.00 g (0.032 mol) of 8-chloro-l, 2,3,4,5,6-hexahydrobenzo [f] quinoline in 50 ml of pyridine and added dropwise at 0 ° 6.75 g (0.048 mol) of benzoyl chloride , After stirring overnight at room temperature, it is extracted with water and chloroform, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1: 1) and crystallization (chloroform-hexane) gives <1-benzoyl-8-chloro-1,2, 3,4,5,6-hexahydrobenzoic] chi noil η as

white crystals of melting point 194-196 °.

b) Dissolve 7.80 g (0.024 mol) of 4-benzoyl-8-chloro-l, 2,3, -4,5,6-hexahydrobenzo [f] quinoline in 100 ml of chloroform and dropwise at 0 ° a suspension of 9.80 g (0.05 mol) of 8% p-ra-chloroperbenzoic acid in 100 ml of chloroform. After stirring for 3 hours at room temperature, it is extracted with 2N sodium hydroxide solution and water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica gel, chlorofotm-hexane, 1: 2) and crystallization (ethyl acetate-hexane) gives 4-benzoyl-II-chloro-1, 2,4, -5,6,7-hexahydro-4-benzazecine-3, 8-dione as white crystals of melting point 129-131 °.

Example 9

a) Dissolve 7.00 g (0.032 mol) of 8-chloro-l, 2.3,4,5,6-hexahydrobenzo [fJquinoline in 50 ml of pyridine and added dropwise at 0 ° 7.42 g (0.048 mol) of phenylacetyl chloride. After stirring overnight at room temperature, it is poured into water, extracted with ethyl acetate, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica gel, chloroform-hexane 1: 1) gives 8-chloro-4- (phenylacetyl) -1,2,3,4,5,6-hexahydrobenzo [fjquinoline in the form of an oil.

b) 7.10 g (0.021 mol) of 8-chloro-4- (phenylacetyl) -1,2,3,4,5,6-hexahydrobenzo [f] quinoline are dissolved in 100 ml of chloroform and added dropwise at 0 ° Suspension of 8.55 g (0.043 mol) of 85% strength m-chloroperbenzoic acid in 100 ml of chloroform. After stirring for 3 hours at room temperature, extracted with 2N sodium hydroxide solution and water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica gel, chloroform-hexane 1: 1) and crystallization (eeeigester-hexane) gives ll-chloro-1,2,4,5,6,7-hexa-

3S hydro-4- (phenylacetyl) -4-benzazecine -3,8-dione as white crystals of melting point 178-180 °.

To a solution of 4.75 g (0.03 mol) of potassium permanganate and 514 g (2.4 mol) of sodium periodate in 12 l of water are added 26.3 g (0.12 mol) of 8-chloro-l, 2.3 , 4, 5,6-Hexahydrober zo [f] -c'i-inoline, dissolved in 3 1 of methylene chloride, adds 3.00 g (0.013 mol) Benzyltriäthylammoniumchlorid and stirred overnight at room temperature. It is filtered over dicalite and extracted with methylene chloride. Drying with sodium sulfate, distilling off the solvent in vacuo and chromatographing (silica gel, ethyl acetate) gives U-chloro-1,2,4,5,6,7- hexahydro-4-benzazecine-3,8-dione. as beige crystals of melting point 142-144 °.

Example 11 A solution of 2.05 g (7 mmol) of 4-acetyl is added.

-II-chloro-1-αE-hexahydro -benzazecine-S.beta-dione in 30 ml of methanol with 0.85 g (15.4 mmol) of sodium methoxide, stirred for 2 hours at room temperature, the reaction mixture concentrated in vacuo , mixed with water and extracted at pH 14 with chloroform. After drying the chloroform phase with sodium sulfate and distilling off the solvent under reduced pressure gives ll-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione of melting point 142-144 °.

Example 12

a) Dissolve 15.0 g (0.06 mol) of 8-chloro-l, 2,3,4,5,6-hexahydrobenzo [f] quinoline in 150 ml of methylene chloride, added with 6.68 g (0.066 mol) Triethylamine and added dropwise at 0 ° 11.2 g (0.066 mol) of p-methoxybenzoyl chloride in 50 ml of methylene chloride. After 1 hour of stirring at room temperature, extracted with water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Crystallization (methylene chloride ether) gives 4- (p-methoxybenzoyl) -8-chloro-1,2,3,4,5,6-hexahydrobenzo [f-quinoline as white crystals

- 31 - 2 6 4 4 of melting point 1Ρ2-1Θ3 ⁰ .

b) 8.80 g (0.025 mol) of 4- (p-methoxybenzoyl) -8-chloro-1,2,3,4,5,6-hexahydrobenzo [f] -chlorinol are dissolved in 100 ml of chloroform and added dropwise at 0 ° a suspension of 10.3 g (0.051 mol) of 85% strength m-chloroperbenzenic acid in 100 ml of chloroform. Nar ι "ündündigem stirring at room temperature, extracted with 2N sodium hydroxide solution and water, dried with magnesium sulfate and the solvent is distilled off in vacuo.

Chromatography (Kieeelgel, Aother-Hexane, 2: 1) and

Crystallization (ether-hexane) gives 4- (p-methoxybenzoyl) - -ll-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione as a white crystals of melting point 143 °.

Example 13

a) Dissolve 8.78 g (40 raHol) of 8-chloro-l, 2,3,4,5,6-hsxahydrobenzo [f] quinoline in 88 ml of methylene chloride and dropwise at 0 ° 7.70 g (44 mmol). Chlorobenzoyl chloride in 60 ml of methylene chloride. After stirring for 1 hour at room temperature, it is extracted with water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica gel, chloroform-hexane 2: 1) and crystallization (chloroform-hexane) gives 8-chloro-4- (p-chlorobenzoyl) -1,2,3,4,5,6-hexahydrobenzo [f-quinoline as wise crystals of melting point 189-191 °.

b) Dissolve 5.20 g (14.5 mmol) of 8-chloro-4- (p-chlorobenzoyl) -1,2,3,4,5,6-herahydrobenzo [f] quinoline in 50 ml of chloroform and drip at 0 "a suspension of 5.90 g (29 mmol) of 85% strength m-chloroperbenzoic acid in 50 ml of chloroform After 1 hour of stirring at room temperature, extracted with 2N sodium hydroxide solution and water, dried with magnesium sulfate and the solvent is distilled in vacuo chromatographic

3 * 5 phage (silica gel, chloroform) and crystallization (ether-hexane) gives ll-chloro-4- (p-chlorobenzoyl) -1, 2,4,5,6,7- hexahydro -A-benzazecine-3 , 8-dione as white crystals from

Melting point 141-143 °.

Bet game 14

a) Dissolve 14.3 g (0.066 mol) of e-chloro-1,2,3,4,5,6-hexa · -hydcobenzo [f] quinoline in 143 ral methylene chloride, treated with 6.68 g (0.066 mol) of triethylamine and dripping at 0 °, 11.3 g (0.066 mol) of m-methoxybenzoyl chloride in 60 ml of methylene chloride. After stirring at room temperature for 1 hour, it is extracted with water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica gel, 19: 1 toluene ester) and crystallization (methylene chloride ether) gives 4- (m -methoxybenzoyl) -8-chloro-1,2,3,4,5,6-hexahydrobenzo [£] quinoline as white crystals of melting point 133 °.

b) 3.20 g (0.009 mol) of 4- (m-methoxybenzoyl) -8-chloro-1,2,3,4,5,6-hexahydrobenzo [f] quinoline are dissolved in 35 ml of methylene chloride and added dropwise at 0 ° a suspension of 3.77 g (0.019 mol) of 85 percent strength. m-chloroperbenzoic acid in 35 ml of methylene chloride. After 1 hour of stirring at room temperature, extracted with 2N sodium hydroxide solution and water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Crystallization (methylene chloride ether) gives 4- (m-methoxybenzoyl) -II-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione as white crystals of melting point 105-106 °.

Example 15

a) Dissolve 5.00 g (0.02 mol) of 8-chloro-1.2.3.4.5.6-hexahydro [flchinoline in 70 ml of methylene chloride, treated with 2.23 g (0.022 mol) of triethylamine and added dropwise at 0 ° 3.85 g (0.022 mol) of o-methoxybenzoyl chloride in 20 ml of methylene chloride. After stirring for 1 hour at room temperature, it is extracted with water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Chromatography (silica

- 33 -

26443

gel, toluene-ethyl acetate, 9: 1) and crystallization (methylene chloride-ether) gives 4- (o-methoxybenzoyl) -8-chloro-l.2,3.-4,5,6-hexahydrobenzoic] quinoline as wise crystals of Melting point 139 °.

b) Dissolve 5.75 g (0.016 mol) of 4- (o-methoxybenzoyl) -8-chloro-1,2,3,4,5,6-hexahydrobenzoic] quinoline in 60 ml of methylene chloride and trop.'t at 0 ° a suspension of 6.70 g (0.033 mol) of 85 percent. m-Chlorperbenzoesäuce in 60 ml of methylene chloride. After 1-otündigem stirring at room temperature, extracted with 2N sodium hydroxide solution and water, dried with magnesium sulfate and the solvent is distilled off in vacuo. Crystallization (methylene chloride ether) gives 4 ~ (o-methoxybenzoyl) -II-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione as a white crystals of melting point 179 °.

Example 16

a) To 110.7 g of aluminum chloride in 800 ml of methylene chloride are added dropwise with stirring between 0 ° and 5 ° within 50 minutes 96.9 g of p-bru / aphenylessigsäurechlorid, dissolved in 200 ml of methylene chloride. Thereafter, Aethyien is introduced into the mixture between 0-5 ° for 30 minutes, followed by stirring for 1 hour at room temperature and then added between 0 ° and 3 ° 600 ml of cold water. The methylene chloride phase is separated off and washed with 2 × 350 ml 2N hydrochloric acid and 2 × 350 ml saturated sodium bicarbonate solution. The water phases are extracted with 200 ml of methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate and concentrated in vacuo. The 6 ~ bromo-3,4-dihydro-2 (1H) -naphthalenone crystallized from 400 ml of low-boiling petroleum ether shows a

Melting point of 75-77 °

 35

b) 35.0 g of 6-bromo-3,4-dihydro-2 (1H) -naphthalenone are dissolved in 250 ml of benzene and 12.5 ml of pyrrolidine in the presence of 0.5 g

- 34 -

26 443

p-Tolulsulfonsäure boiled for 3 hours at reflux. After evaporation of the T-oxy in vacuo, the residue is stirred in diethyl ether. The crystallized 1- (6-bromo-3,4-dihydro-2-naphthyl) pyrrolidine has a melting point of 125-127 °. From the mother liquor, a further portion of the above product of melting point 127-128 ° can be isolated by stirring in isopropyl ether.

c) To 35.5 g of 1- (6-bromo-3,4-dihydro-2-naphthyl) pyrrolidine

17.5 g of acrylamide and 0.65 g of p-toluenesulfonic acid are added. It is heated under nitrogen for 2 hours at 100 ° and at 150 °. The reaction mixture is treated with 250 ml of chloroform, whereupon the insoluble fractions are filtered off. This gives 8-bromo-l, 4,5,6-tetrahydrobenzo [f] quinolin-3 (2H) -one of melting point 227-228 °. After recrystallization from ethanol, the product has a melting point of 23Ot231 °.

d) To a suspension of 5.2 g of lithium aluminum hydride in 140 ml of dry tetrahydrofuran, stirred at 20 ° under nitrogen, 19.0 g of 8-bromo-l, 4,5,6- are added in portions within the range of 20 ° to 25 ° within 35 minutes. tetrahydrobenzo [f] quinoline-3 (2H) -one. The reaction mixture is then heated to reflux for 150 minutes under reflux, then cooled and then added between 0 ° and 10 ° with 17 ml of 6.5 N sodium hydroxide solution. The resulting suspension is filtered, after which the filter residue is washed several times with tetrahydrofuran and the filtrate is evaporated in vacuo. The resulting 8-bromo-l, 2,3,4,5,6-hexahydrobenzo [f] quinoline is processed directly.

e) 13.9 g of crude 8-bromo-l, 2,3,4,5,6-hexahydrobenzo [f] quinoline are taken up in 29 ml of pyridine and 27.0 ml of acetic anhydride. The reaction mixture is allowed to stand for 20 hours at room temperature, evaporated. takes the remaining residue twice in 100 ml of dry toluene and the resulting solutions evaporated to dryness. The return

.35- 2 6 443

is dissolved in ethyl acetate and chromatographed on 200 g of silica gel (particle size 0.2-0.5 mm). The ethyl acetate-eluted 4-acetyl-8-bromo-l, 2,3,4,5,6-hexahydrobenzo- [f] quinoline shows after recrystallization from isopropyl ether has a melting point of 96-97 °.

f) 8.0 g of 4-acetyl-8-bromo-1,2,3,4,5,6-hexahydrobenzo [f] -quinoline are dissolved in 80 ml of chloroform, whereupon between 0 ° and + 5 ° 11.2 g 85 % m-chloroperbenzoic acid dissolved in 80 ml of chloroform is added dropwise. The mixture is then stirred at room temperature for 4 hours, whereupon 1.0 g of potassium iodide and 200 ml of water are added and then treated with sodium thiosulfate until decolorization. The chloroform phase is separated and washed with 100 ml of 2N sodium hydroxide solution and with 200 ml of water. The water phases are extracted with 100 ml of chloroform. The combined chloroform extracts are dried and evaporated in vacuo. The recrystallized from Eoeigester 4-acetyl-ll-bromo-l.2.4,5,6,7-hexahydro-4-benzazecine-3,8-dione shows a melting point of 162-164 °.

Example 17

a) 12.0 g of 6-methoxy-2-tetralone are refluxed in 200 ml of benzene and 5.6 ml of pyrrolidine in the presence of 0.5 g of anhydrous p-toluenesulfonic acid for 2 hours. The toluene is removed in vacuo. To the thus obtained crude 1- (6-methoxy-3,4-dihydro-2-naphthyl) pyrrolidine are added 9.70 g of acrylamide and 0.5 g of p-toluenesulfonic acid. It is heated under nitrogen for 2 hours to 100 ° and to 150 °. The reaction mixture is partitioned between 400 ml of chloroform and 40 ml of water. The organic phase is washed with 2 × 40 ml of water and the water phases are extracted with 1 × 100 ml of chloroform. The chloroform phases are triturated, dried over sodium sulfate and concentrated. The residue is chromatographed on 160 g of silica gel (particle size 0.2-0.5 mm). which eluted with methylene chloride and off

j,. 2 6 4 4 3

Essigester umkrietallieierte 8-methoxy-l, 4,5,8-tetrahydrobenzoff] ohinolin-3 (2H) -one shows a melting point of 208-209 °.

b) To a stirred at 20 ° under nitrogen suspension of 1.69 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran within 35 minutes between 20 ° and 25 ° portionwise 5.1 g of 8- (methoxy-l, 4,5,8-tetrahydi The reaction mixture is then heated to reflux for 150 minutes under reflux, then cooled and then added between 0 ° and 10 ° with 1.5 ml of 6, SN sodium hydroxide solution. The resulting suspension is filtered, after which the filter backsheet is washed several times with tetrahydrofuran and the filtrate is evaporated in vacuo.The thus obtained 8-methoxy-1,2,3,4,5,6-hexahydrobenzo [fjquinoline is processed further directly

c) 4.7 g of 8-methoxy-l.2,3,4,5,6-hexahydrobenzo [f-quinoline are taken up in 15 ml of pyridine and 11 ml of acetic anhydride. The reaction mixture is allowed to stand for 20 hours at room temperature, then evaporated, the remaining residue is taken up twice in 50 ml of dry toluene and the resulting solutions evaporated to dryness. The residue is dissolved in methylene chloride and chromatographed on 50 g of silica gel (particle size 0.2-0.5 mm). The methylene chloride-eluted 4-acetyl-8-methoxy-1,2,3,4,5,6-hexahydrobenzo [f] quinoline shows after recrystallization from Isopropyläthec a melting point of 119-120 °.

d) 21.3 g of 4-acetyl-8-methoxy-1,2,3,4,5,6-hexahydrobenzo [f] quinoline are dissolved in 200 ml of chloroform, whereupon at 0 ° to + 5 ° 38.0 g of 85% strength by weight Chloroperbenzoic acid, dissolved in 250 ml of chloroform, added dropwise. Thereafter, stirring is carried out at room temperature for 18 hours, whereupon sodium iodide and water are added and then treated with sodium thiosulfate until decolorization. The chloroform phase is never washed with aqueous ammonia and sodium chloride solution. The

- 37 -

Water phases are extracted with chloroform. The combined chloroform extracts are dried over sodium sulfate and evaporated in vacuo. The Eseigestei: recrystallized 4-acetyl-ll-methoxy-l.2,4.5.6,7-hexahydro-4-benzazecine -3,8-dione shows a melting point of 156-158 °.

Example 18

a) 20.6 g of 5-chloro-1-tetralone are dissolved in 100 ml of alcohol

dissolved, whereupon 2.2 g of sodium borohydride are added in portions. The reaction mixture is stirred for 2 hours at 40 °, then cooled and then treated at room temperature with 32 ml of 2N hydrochloric acid. Then concentrated in vacuo and extracted with methylene chloride. The organic phases are dried over sodium sulfate and evaporated. The residual 5-chloro-1-tetralol is further processed directly as a crude product.

b) 20.6 g of crude 5-chloro-1-tetralol are dissolved in 400 ml of toluene, and 1.60 g of p-toluenesulfonic acid are added to this solution. The mixture is refluxed for 2 hours, collecting 1.9 ml of water with a water separator. Add 3 g of molecular sieve 4A and reflux for a further 30 minutes. The reaction mixture is cooled; The organic phase is washed once with 100 ml of saturated aqueous sodium bicarbonate solution and twice with 50 ml of water each time, dried, and evaporated in vacuo. The remaining 5-chloro-3,4-dihydronaphthalene remaining is distilled in a bulb tube. Boiling point 100 ° / 0.05mmHg.

c) To 23.2 g of m-chloroperbenzoic acid (85%) dissolved in

320 ml of methylene chloride, between 0 ° and + 5 ° within 20 minutes dropwise 17.0 g of 5-chloro-3,4-dihydronaphthalene, dissolved in 300 ml of methylene chloride added. The mixture is then stirred for 3.5 hours at room temperature and then washed six times with 100 ml of 5% water!

- 38 -

26 443t

washed according to ammonia. The methylene chloride phase is dried over sodium sulfate, filtered and evaporated in vacuo. The remaining ale residue 5-chloro-oxirano [a] - 2,3 · dihydronaphthalene is further processed as a crude product. 5

d) 24 g of crude 5-chlorooxir * no [a] -2,3-dihydronaphthalene

are dissolved in 350 ml of toluene. A freshly prepared magnesium bromide solution is added dropwise to this solution under nitrogen at room temperature. 8.25 g (25.5 g) of bromine are added in 800 ml of diethyl ether under nitrogen, followed by boiling for 30 minutes and the insoluble fractions is decanted]. Anochlieeaend is stirred for 1 hour at room temperature. The Diöthyläther is distilled off in vacuo and continuously replaced by 1000 ml of toluene. The resulting mixture is refluxed for 2 hours, cooled to room temperature and then washed with 300 ml and 2 × 100 ml of cold water. The aqueous phases are back-extracted with 150 ml of toluene. The combined organic phases are dried over sodium sulfate and concentrated. The residue is chromatographed over 100 g of silica gel (particle size 0.04-0.063 mm). The 5-chloro-2-tetralone eluted with toluene is distilled in a kugelrohr for further purification (boiling point 145-150 ° / 0.04 mmHg); The crystallized product shows a melting point of 32-34 ° (sintering from 31 °).

e) 11.07 g of 5-chloro-2-tetralone are refluxed in 200 ml of benzene and 10.1 ml of pyrrolidine in the presence of 0.3 g of p-toluenesulfonic acid for 2 hours. The resulting crude i_ (5-chloro-3,4-dihydro-2-naphthyl) pyrrolidine is treated without purification with 9.0 g of acrylamide and 0.5 g of p-Toluolsulfonsäuce. It is heated under nitrogen for 2 hours at 100 ° and at 150 °. 250 ml of ethyl acetate and 50 ml of water are added to the reaction mixture, whereupon the insoluble fractions are filtered off, washed with ethyl acetate and water, dried and recrystallized from ethyl acetate. This gives 7-chloro-1, 2,5,6-tetrahydro-

, ". 2 ί 4 4 3 1

benzoylnolene-3 (4H) -one of melting point 252-253 °.

C) To a stirred under nitrogen suspension of

1.30 g of lithium aluminum hydride In 60 ml of dry tetrahydrofuran are added in portions between 20 ° and 25 ° within 35 minutes 4 g of 7-chloro-l, 2,5,6-tetrahydro-benzo []] -chloroline-3 (4H) - on. The Reaktlonsgemißch is then heated to reflux for 150 minutes under reflux, then cooled and hiorauf zwischer. 0 ° and 10 ° with 4.2 ml S, added 5N sodium hydroxide solution. The resulting suspension is filtered, after which the residue is washed with 5 × 20 ml of tetrahydrofuran and the flltrac is evaporated in vacuo. The crude 7-chloro-l, 2,3,4,5,6-hexahydrobenzo [f] -chlorinol thus obtained is taken up in 10 ml of Pytiuln and 9.0 ml of Esslgsäureanhydrid. The reaction mixture is allowed to stand for 20 hours at room temperature, evaporated, the residue remaining aufe twice in 50 ml of dry toluene and the solutions evaporated to dryness. The residue is dissolved in methylene chloride and chromatographed on 70 g of silica gel (particle size 0.04-0.063 mm). The chloroform-eluted 4-acetyl-7-chloro-1,2,3,4,5,6-hexahydrobenzo [naphtha, after recrystallization from isopropyl ether, has an melting point of 89 ° -90 °,

g) 3.4 g of 4-acetyl-7-chloro-l, 2,3,4,5,6-hexahydrobenzo [f] · chinolln are dissolved in 100 ml of chloroform, whereupon at 0 ° to - (- 5 ° 6.8 g 85 After stirring for 3 hours at room temperature, 1.5 g of potassium iodide and 40 ml of water are added followed by crosslinking with sodium thiosulfate until decolorization is carried out 2N sodium hydroxide solution and 2 × 80 ml of water, which are shaken out with 100 ml of chloroform, and the combined chloroform extracts are dried and evaporated in vacuo, which is recrystallised from ethyl acetate

- 40 -

2 * 443

4-Acetyl-12-chloro-l, 2,4,5,6,7-hexahydro-4-ben / azocln-3,8-dlon 2 <has a melting point of 160-162 °.

Example 19

a) In 1125 ml of ethanol 75.0 g of 5-methoxy-L-tetralone are dissolved, whereupon at room temperature 0.05 g Natrlumbochridrid zugegebon be added. Dao Reaktlonegeraisch is heated to 40 ° for 3.5 hours, then cooled to room temperature and then at 20-26 ° with 120 in). 2N hydrochloric acid added. Then concentrated in vacuo and extracted with methylene chloride. The organylphosphates are dried over sodium sulfate and evaporated. The residue remaining l, 2,3,4-tetrahydro »5-methoxy-l-naphthallnol shows after recrystallization from η-hexane has a melting point of 78.5-79 °.

b) 51.0 g of 1.2.3,4-tetrahydro-5-methoxy-l-naphthallnol was boiled in 1.7 1 of toluene with 4.0 g of p-ToluolsulfonaUure 2 fltunden on a water. The reaction mixture is washed with 200 ml of saturated sodium carbonate solution and with 2 × 200 ml of water. The toluene phase is dried over sodium sulfate and evaporated in vacuo, leaving crude 7.8 ~ dihydro-l-naphthylmethylethyl ether residue.

For purification, the crude product obtained is over 600 ς

Klesolgel (grain size 0.2-0.5 mm) Chromatography. The η-hexane-eluted 7,8-Dlhydro-n-naphthylmethyläther is further processed directly without further purification. A sample is distilled in a bulb tube and shows a boiling point of U0 ^e / 0.05IBiTiHg.

c) To 50.3 g of 85% longer m-chloroperbenzoic acid In 800 ml of methylene chloride are added dropwise between 0 ° and> 5 ° 36 g of 7,8-dihydro-l-naphthylmethyläther, dissolved in 600 ml of methylene chloride. The reaction probe is stirred for 5.5 hours at room temperature and then washed with 6 × 200 ml of 5% aqueous ammonia. The Waseer phases are mixed with 300 ml Metnylon

- 41 -

chlocld extracted. Did not organic phases are combined, dried over sodium sulfate and concentrated. The resulting (t-methoxyoxlcano [a] -2,3-dlhydronaphthane is dissolved in 100 ml of toluene without prior purification. To this solution is added dropwise at room temperature a feverishly prepared magnesium bromide solution [9.2 g Magneireuras In 17.8 ml (55.2 g) of bromine, 17.8 ml (55.2 g) of bromine are added to 1.1 g of diethyl ether in nitrogen, followed by boiling for 30 minutes and decanting from the insoluble fractions].

Aneclillessend is stirred for 1 hour at room temperature. The diethyl ether is depleted in vacuo and replaced continuously with 2 liters of toluene. The resulting solution is boiled for 3 hours under reflux, then cooled to room temperature and washed with 200 ml of cold water, whereupon the aqueous phases are extracted with 300 ml of toluene. The organic phases are combined, dried over sodium sulfate and concentrated. The remaining crude 3,4-dihydro-S-methoxy-2- (1H) -naphthallnone is chromatographed over 500 g of clover gel (Korngjösse 0.2-0.5 mm). The toluene-elutrierte product is distilled for further purification in a Kugelrohr and then shows a melting point of 37.5-38.5 °.

d) 10.18 g of 3,4-dlhydro-5-methoxy-2 (UI) -naphthallnone are refluxed for 2 hours in 200 ml of benzene and 4.8 ml of pyrrolidine in the presence of 0.25 g of p-toluene-2-carboxylic acid. The toluene is distilled off in vacuo and the residue is stirred in boiling petroleum ether. The 1- (5-methoxy-3,4-dlhydro-2-naphthyl) pyrrole is sputtered off

and shows a melting point of 77-78 °. 30

e) To 9.9 g of 1- (5-methoxy-3,4-dlhydro-2-naphthyl) pyrrolidine are added 7.3 g of acrylamide and 0.4 g of p-toluenesulfonic acid. The mixture is heated under nitrogen for 2 hours at 100 ° and at 150 ° and then 150 ml of chloroform and 30 ml of water. The precipitated 1,4,5,6-tetrahydro · 7

- 42 -

26443

-methoxy-3 (2H) -quinolinone is filtered off and shows a melting point of 248-250 °.

To a stirred at 20 ° under nitrogen suspension of 3.1 g of lithium aluminum hydride in 120 ml of dry tetrahydrofuran within 35 minutes between 20 ° and 25 ° portionwise 9.1 gl, 4,5,6-tetrahydro-7-methoxy-3 (2H) - quinolinone added. The reaction mixture is then boiled under reflux for 150 minutes, then cooled and then added between 0 ° and 10 ° with 9.7 ml of 6.5N sodium hydroxide solution. The resulting suspension is filtered, followed by washing the FilterrUcketand several times with 30 20 ml of tetrahydrofuran and the combined filtrates evaporated in vacuo. The 1,2,3,4,5,6-hexahydro-7-methoxybenzo [fjquinoline thus obtained is processed further directly.

g) 9.0 g of l, 2,3,4,5,6-hexahydro-7-methoxybenzo [f] quinoline are taken up in 20 ml of pyridine and 17.5 ml of acetic anhydride. The reaction mixture is allowed to stand at room temperature for 20 hours, then evaporated, the remaining residue is taken up twice in 75 ml of dry toluene and the resulting solutions are evaporated to dryness. The residue is dissolved in ethyl acetate and chromatographed on 100 g of silica gel (particle size 0.2-0.5 mm). The ethyl acetate-eluted and recrystallized from isopropyl ether 4-acetyl-l, 2,3,4,5,6-hexahydro-7-methoxybenzo [f] chinoI in shows a melting point of 128-130 °.

h) 4.87 g of 4-acetyl-l, 2,3,4,5,6-hexahydro-7-methoxybenzo [f] -quinoline are dissolved in 120 ml of chloroform, whereupon at 0 ° to + 5 ° 9.55 g 85 % m-chloroperbenzoic acid dissolved in 120 ml of chloroform are added dropwise. Thereafter, it is stirred at room temperature for 3 hours, whereupon 1.6 g of potassium iodide and 40 ml of water are added and then treated with sodium thiosulphate until decolorization. The chloroform phase is extracted with 40 ml of ZN sodium hydroxide solution and 2 × 100 ml of Waseer.

see. The heat phases are extracted with 100 ml of chloroform. The combined chloroform extracts are dried and evaporated in vacuo. The backsheet is chromatographed on 60 g of silica gel (particle size 0.2-0.5 mm). The eluted with methylene chloride and recrystallized from Eeeigester 4-acetyl-l, 2,4,5,6,7-hexahydro-l2-raethoxy -4-benzazecine-3,8-dione shows a melting point of 170-172 °.

Example 20 10

a) To 115 g of aluminum chloride in 700 ml of methylene chloride are added dropwise with stirring at 0 ° to 5 ° within 60 minutes 149.4 g of 2,4-dichlorophenylacetyl chloride, dissolved in 200 ml of methylene chloride. Thereafter, ethylene is introduced between 0 ° and 5 ° for 30 minutes, followed by stirring for 1 hour at room temperature and then mixed between 0 ° and 5 ° with 300 ml of water of ice. The methylene chloride phase is washed with 2N hydrochloric acid, with hater, with saturated sodium bicarbonate solution and again with water. The aqueous phases are extracted with methylene chloride. The methylene chloride phases are combined, dried and evaporated. The residue is stirred with 100 ml of low-boiling petroleum ether, later more 250 ml of low-boiling petroleum ether and leaves 72 hours in a refrigerator. The solid is filtered off and filtered while eluting with chloroform over 600 g of silica gel (particle size 0.2-0.5 mm). 6,8-Dichloro-3,4-dihydro-2 (1H) -naphthalenone is obtained which, after recrystallization from low-boiling petroleum ether at 0 ° to 5 °, has a melting point of 90-92 °.

b) 30.0 g of 6,8-dichloro-3,4-dihydro-2 (1H) -naphthalenone are dissolved in 250 ml of benzene and 11.5 ml of pyrrolidine in the presence of 0.5 g of anhydrous p-toluenesulfonic acid for 2 hours Reflux cooked. The resulting 1- (6,8-dichloro-3,4-dihydro-2-naphthylpyrrolidine is triturated with 150 ml of isopropyl ether for purification, and the filtered solid shows a melting point of 84 ° -86 °

- 44 -

26443t

further portion of the melting point 84.5-85.5 ° are isolated.

The two portions are combined, and after recrystallization from isopropyl ether gives l- (6,8-dichloro-3,4-

-dihydto-2-naphthyl) pyrollinaine of melting point 85.5-86 °. 5

c) To 30.6 g of 1- (6,8-dichloro-3,4-dihydro-2 (1H) -naphthyl) -pycrolidine are added 16.2 g of acrylamide and 0.9 g of anhydrous p-toluenesulfonic acid. One heated. under nitrogen 2 hours at 100 ° and 150 °. After cooling, the reaction mixture was stirred at room temperature in 80 ml of a mixture of chloroform-ethyl acetate {1: 1) . This gives 8,10-dichloro-l, 4.5,6-tetrahyd :: obenzo [f Jchinolin- -3 (2H) -one, which melts after recrystallization from ethyl acetate at 212-214 °.

d) To a stirred under nitrogen at 20 ° suspension of 2.26 g lithium aluminum hydride in 67 ml of dry tetrahydrofuran over 35 minutes between 20-25 ° portionwise 8.0 g of 8,10-dichloro-l, 4,5,6 tetrahydrobenzofichinoHn-3 (2H) -one was added. The reaction mixture is then heated for 150 minutes under reflux to the boiling point, then cooled υ \ d between 0 ° and + 10 ° with 7.38 ml of 6.5 N sodium hydroxide added. The resulting suspension is filtered and the filtrate is evaporated in vacuo. The resulting 8,10-dichloro-1,2,3,4,5,6-hexahydrobenzof-quinoline is taken up in 16 ml of pyridine and 14 ml of acetic anhydride, allowed to stand at room temperature overnight, evaporated, and the remaining residue is taken twice in} e 50 ml of toluene and the solutions evaporated to dryness. The residue is dissolved in chloroform and chromatographed on 100 g of silica gel (particle size 0.2-0.5 mm). The chloroform-eluted 4-acetyl-8,10-dichloro-l, 2,3,4,5,6- & e-kta-hydrobenzo [fJquinoline shows after recrystallization from isopropyl ether a melting point of 99-101 °.

e) 4.2 g of 4-acetyl-8,1O-dichloro-1,2,3,4,5,6-fcofcfcahydrobenzo

- 45 -

[]] Quinoline are dissolved in 80 ml of chloroform, followed by dropwise addition of 7.45 g of 85% m-chloroperbenzoic acid dissolved in 80 ml of chloroform at to + 5 °. Thereafter, it is stirred at room temperature for 3 hours, whereupon 1.5 g of potassium fluoride and 50 ml of water are added and then treated with sodium thiosulfate until decolorization. The chloroform phase is washed with 40 ml of 2N sodium hydroxide solution and 2 × 100 ml of water. The water phases are extracted with 100 ml of chloroform. The combined chloroform extracts are dried and evaporated in vacuo. The recrystallized from isopropyl ether 4-acetyl-9, ll-dichloro-l, 2,4,5,6,7-hexahydro-4-benzazecine -3,8-dione shows a melting point of 152-153 °.

Example A

Tablets of the following composition are prepared which contain as active ingredient 4-acetyl-1-chloro-1, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione.

20 1. Active ingredient (micronized) per tablet Second lactose 50 mg Third corn starch 120 mg 4th polyvinylpyrrolidone 50 mg 5th Sodium carboxymethylßtärke 8 mg 25 6th magnesium stearate 20 mg 2 mg

250 mg

The active ingredient is mixed homogeneously with a mixture of milk sugar and corn starch. Sieben, moistened with an aqueous solution of polyvinylpyrrolidone, granulated and dried. The dried granules are mixed with sodium carboxymethyl starch and magnesium stearate and the resulting mixture is made into tablets of suitable size. Cracking groove pressed.

Example B

Tablets of the following composition are prepared which contain, as active ingredient, 4-acetyl-II-chloro-1, 2,4,5,6,7-hexahydro-5 -4-benzazecine-3,8-dione.

Active ingredient (micronized) per tablet 1. lactose 10 mg Second Microcrystalline cellulose 88 mg Third Maiestärke 60 mg 4th Sodium carboxymethyl starch 20 mg 5th magnesium stearate 20 mg 6th 2 ma

200 mg

The active ingredient is mixed homogeneously with milk sugar. Sieben, then mixes a mixture of microcrystalline cellulose, corn starch and sodium carboxymethyl starch and mixed with the magnesium stearate. The thus obtained press-ready mixture is processed into tablets of suitable size with scored groove.

Claims (19)

claims 1. A process for the preparation of Benzazöcin derivatives of the general formula 1 °
R Il _R 2 I C-CH ₉ - CH ₉ ^R \ φ \ / ^{2 2 N} CH _{2 R} 3 / \ y \ /NO⁵ * ^ 4 ^CH 2 " ^CH 2" ^ 12 3 wherein R and R are each hydrogen or chlorine, R 4 is hydrogen, fluorine, chlorine, bromine or methoxy, R 5 is hydrogen, chlorine or methoxy and R is hydrogen, acetyl, propionyl, benzoyl, chlorobenzoyl, methoxybenzoyl or phenylacetyl, with the proviso that 2 or 3 of the symbols R to R are hydrogen . characterized in that one
20 a) a benzoquinoline derivative of the general formula R ¹ / \ • · ·
I Π I wherein R, R, R, R and R have the above meaning, oxidized or b) of a benzazecine derivative of general formula 35 2 I C-CH ₀ - CH ₀ \
R _n '/ \ / ^{2 l} CH ₂ RI CH ₀ --CH ₀ - C
RO 12 3 4
wherein R, R, R and R have the above meaning and Z represents a removable group which removes the group designated Z. 10 1 2 3 4 daee R chlorine and R. R and R each water substance 2. The method according to claim 1, characterized in that j R ¹ c
mean. 3. Method according to claim 1, characterized in that RC
mean. that R is chlorine and R, R and R are each hydrogen 4. Method according to claim 1, characterized in that 3 12 that R is fluorine, chlorine, bromine or methoxy and R, R and R are each hydrogen. 5. Method according to claim 1, characterized in that Λ TOO R is chlorine or methoxy and R, R and R are each hydrogen. 6. Process according to claim 1, characterized in that t R ¹ u
mean.
30 13 2 4 R and R are each chlorine and R and R are each hydrogen 7. The method according to any one of claims 1 to 6, characterized in that R 'is acetyl. 8. The method according to claim 1, characterized in dacs one prepares 4-acetyl-9-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione. 9. The method according to claim 1, characterized in that one prepares 4-acetyl-ll-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione. 10. The method according to claim 1, characterized in that one prepares 4-acetyl-ll-fluoro-1,2,4,5,6,7-hexahydro-4-benzazecine-3-dione. 11. The method according to claim 1, characterized that 4-acetyl-9, ll-dichloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3.8-dione prepared. 12. The method according to claim 1, characterized in that one prepares 4-acetyl-ll-raethoxy-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione. 13. The method according to claim 1, characterized in that one produces ll-chloro-1,2,4,5,6,7-hexahydro-4-propionyl-4-benzazecine-3,8-dione. 20 14. The method according to claim 1, characterized in that one prepares 4-benzoyl-ll-chloro-l, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione. is. Process according to Claim 1, characterized in that 4- (o-methoxybenzoyl) -II-chloro-1, 2,4,5,6,7-hexahydro-4-benzazecine-3.8-dione is prepared. 16. The method according to claim 1, characterized to prepare 4- (m-methoxybenzoyl) -II-chloro-1, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione. 17. The method according to claim 1, characterized to prepare 4- (p-methoxybenzyl) -II-chloro-1, 2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione. -SO- 10. The method according to claim 1, characterized in that one prepares 11-chloro-4- (p-chlorobenzoyl) -1,2,4,5,6,7-hexahydro-4-benzazec ^J i-3,8-dione , 19. The method according to claim 1, characterized in that one prepares 4-acetyl-1,2,4,5,6,7-hexahydro-12 ~ methoxy-4-benzazecine-3,0-dione. 20. Use of compounds of the general formula I defined in claim 1, ie ^ -acetyl-O-chloro-1,2,3- k , 5,6-hexahydrobenzo / f_ / quinoline, 4-acetyl-1-O-chloro 1,2,3,4,6,6-hexahydrobenzo / f_ / quinoline and O-chloro-4- (p-chlorobenzyl-1, 2,3,4,5,6-hexahydrobenzo / f_ / quinoline, characterized in that they are used for the preparation of medicaments for the control or prevention of cerebral insufficiency or for the improvement of cognitive functions.